Norepinephrine transporter gene (SLC6A2) polymorphisms and promoter methylation in peripheral blood of veterans with posttraumatic stress disorder

Background: Norepinephrine (NE) dysregulation has been implicated as one of the mechanisms in the development of post-traumatic stress disorder (PTSD).Norepinephrine transporter (NET) plays an important role in regulating of NE level at the synapses.The gene of NET is a potential research target for PTSD.However, few studies have examined the genetic variants and DNA methylation of NET regards to the risk of PTSD. Methods:We investigated 16 single-nucleotide polymorphisms (SNPs) across the NET whole gene in 506 veteran patients.Using a subset of individuals (161 patients) from our larger genetic dataset, promoter methylation was performed using pyrosequencing analysis.Results: Significant difference was found in the genotype and allele frequencies for rs168924 and rs192303 by PTSD status, although the significance of rs192303 genotype (p=0.03)disappeared after Bonferroni correction.Neither rs168924 nor rs192303 was a significant predictor of PTSD diagnosis in primary logistic regression.However, significant interaction with Combat Exposure Scale (CES) was observed.The interaction effect was also positively associated with Clinician Administered PTSD Scale (CAPS).Higher CES and lower methylation were significantly associated with risk of PTSD, but no significant interaction effect was observed.Conclusions: To our knowledge, this is the first study to extensively investigate NET gene Polymorphisms and promoter methylation among combat veteran PTSD.Our findings suggest the interaction of combat trauma and risk alleles of NET may account for the increased risk of PTSD.The NET promoter methylation may also participate in the process of PTSD development.